A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11.

Genome-wide nonparametric linkage analysis of 480 sib-pairs affected with type 2 diabetes revealed linkage to a previously unreported susceptibility locus on chromosome 18p11. This result improved with stringent subphenotyping using age- and sex-adjusted BMI, ultimately reaching a logarithm of odds of 3.82 (allele sharing 0.6654) at a point between markers D18S976 and D18S391 when the most obese 20% of the sample was analyzed. Several genes on chromosome 18 have been suggested as metabolic disease candidates, but none of these colocalize with our linkage result. We conclude that our results provide support for the presence of a currently uncharacterized gene on chromosome 18p, certain alleles of which confer increased susceptibility to type 2 diabetes in conjunction with obesity. We additionally observed moderate evidence for linkage to chromosome 1, near marker D1S3462; chromosome 4, near marker D4S2361; chromosome 5, near marker D5S1505; and chromosome 17, near marker D17S1301.

Pulsatile secretion of neuropeptide FF into human blood.

Neuropeptide FF (NPFF) is a peptide with opioid modulating and cardioexcitatory effects, it is present in the central nervous system and in the periphery of several mammalian species. Using a sensitive and specific radioimmunoassay for NPFF-like immunoreactivity (NPFFir) we observed that the peptide concentration fluctuated in a pattern compatible with pulsatile secretion of the peptide in human blood. When NPFF samples were collected every 2 or 5 min for a 95 min period in healthy volunteers the basal NPFF concentration in human blood was 2.2 +/- 0.5 pg/ml and the NPFF pulses (14.6 +/- 10.6 pg/ml) represented a 526 +/- 280% increase over baseline. The NPFF pulses where short, suggesting a rapid degradation of NPFF in the circulation. We observed no twenty-four hour rhythm of NPFF in human blood when NPFF samples were taken during one day every four hours. Fluctuations in NPFF levels found in the 95 min and the 24 h studies did not correlate with plasma vasopressin levels. Our study did not support the concept that vasopressin and NPFF may be co-released from the pituitary. However, the pulsatile character of NPFF secretion in itself suggests a biologic role for neuropeptide FF in humans.

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken together with our recent findings of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM (NIDDM2), the data suggest that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response, that subsequently progresses to diabetes and underlines the importance of subphenotypic classification in studies of diabetes.